The goal of this phase I SBIR proposal is to generate the pharmacokinetic and pharmacodynamic data required to support the filing of an Investigational New Drug application (IND) to the Food and Drug Administration (FDA), of the tumor-penetrating peptide iRGD, in combination with gemcitabine as a new treatment for pancreatic cancer. Pancreatic cancer is a key funding priority for the NCI in 2011. iRGD, increases drug accumulation and penetration specificaly into tumors, when co-administered with chemotherapeutic agents, enhancing anti-tumoral activity and tolerability. Pancreatic cancers are characterized by a dense extracellular matrix and stroma that together with high tumor interstitial fluid pressure, acts as a physical barrier inhibiting drug access to the tumor. Increasing drug access deep into the tumor is essential for improving the clinical outcome of both current and future therapies. Preliminary data show that co-administration of iRGD with gemcitabine, the first-line treatment for pancreatic cancer, augments anti-tumoral activity in a xenograft model of pancreatic cancer. The goal of this proposal is to complete the pharmacokinetic and preclinical efficacy studies required to enable filing of an IND for iRGD in combination with gemcitabine as follows: Phase I Aims: 1. Biodistribution studies and optimization of iRGD dosing in combination with gemcitabine. 2. Demonstrate enhanced anti-tumoral activity of gemcitabine co-administered with iRGD in a mouse model of pancreatic cancer. Phase II of this proposal will focus on completion of the required toxicology studies necessary to support filing of an Investigational New Drug application with the Food and Drug Administration. We expect iRGD- based therapies to define the new standard-of-care in pancreatic cancer. The clinical validation of iRGD as a method to enhance anti-tumoral activity of drugs, will support a broader effort to combine iRGD with other anti- cancer therapies. PUBLIC HEALTH RELEVANCE: Poor penetration of drugs into tumors has recently been recognized as a significant contributing factor to cancer drug resistance. This is particularly true of malignancies such as pancreatic cancer which are characterized by a desmoplastic microenvironment of low microvascular density. Our collaborators have discovered a way of overcoming the drug penetration problem. The goals of this Phase I SBIR proposal is to conduct pre-clinical studies aimed at applying this new technology to the treatment of pancreatic cancer, and in the process, define a new standard of care for this deadly disease.